Tourette Disorder (TD) is a developmental neuropsychiatric syndrome characterized by the combination of persistent vocal and motor tics. While initially considered rare, the world-wide prevalence is now estimated to be 0.3-1 percent. Both as a consequence of potentially disabling symptoms as well as very high rates of psychiatric co-morbidity, particularly with obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), TD represents a significant public health concern. Despite decades of evidence supporting a significant genetic contribution, progress on the identification of risk alleles has been disappointing. This difficulty is thought be, in part, a consequence of complex inheritance as well as substantial genetic and phenotypic heterogeneity. This collaborative application unites a group of expert clinicians specializing in Tourette Disorder (TD) with statistical and molecular geneticists who are motivated by three pressing concerns: 1) That a key rate-limiting factor for TD gene discovery has been the paucity of publicly available, large-scale biomaterial resources of the kind that are now commonplace for many neuropsychiatric disorders; 2) that to be successful, genetics efforts in TD must focus on the contribution of both DNA sequence and structural variation, and both rare and common alleles in large sample populations; and 3) that an increased understanding of the genetic etiology of TD will ultimately translate into novel and more effective approaches to treating this often-debilitating disorder, and consequently will have marked public health benefits. Given these concerns, the application elaborates three specific aims: Specific Aim 1 supports an ongoing collaboration of 7 US and 2 international clinical sites that will result in the recruitment of 4450 individuals with TD over five years. This cohort will include a subset of 2995 parent-child trios, allowing for evaluation of de novo DNA sequence and structural variation. This sample will be made rapidly available to the broad scientific community. Specific Aim 2 will support simultaneous copy number variation (CNV) and genome wide association studies (GWAS) on this cohort. In addition, a next-generation, deep re-sequencing effort is proposed to confirm the relevance of two high priority biological pathways identified in the preliminary studies as well as to follow-up on the most promising transcripts that will emerge from the CNV, SNP and gene expression studies proposed herein. Finally, Specific Aim 3 extends a NIH-funded, exploratory project to analyze the transcriptomes of TD subjects and will collect, freeze and store PAXgene tubes on all subjects to enable future gene expression studies and to become part of the publically available NIMH Center resource. In addition, gene expression analyses will be performed on 300 affected subjects shown to have high priority CNVs, investigating the implications of structural variation for cis, trans and genome-wide expression.